Mitochondrial dynamics in the regulation of mitochondrial function and oxidative phosphorylation

线粒体动力学调节线粒体功能和氧化磷酸化

• 批准号: RGPIN-2019-06737
• 负责人: Khacho, Mireille
• 金额: $ 2.7万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744322
• 关键词: Mitochondrial; dynamics; regulation; mitochondrial; function

Mitochondria are classically known to be the cellular energy producers. These dynamic organelles can modify their structure by alterations in their fission and fusion activities through the mitochondrial fusion proteins MFN and OPA1, and fission protein DRP1. Mitochondria have the ability to constantly modify their architecture in response to physiological demands and recent discoveries have shown a direct link between mitochondrial structure and function. For example, we have shown that changes in mitochondrial structure, under certain conditions, can modify energy metabolism to promote efficient ATP production while reducing reactive oxygen species (ROS). At the molecular level, the efficiency of mitochondria is modified through enhanced inter-assembly of electron transport chain (ETC) complexes (known as respiratory supercomplexes). However, the molecular mechanism of how changes in mitochondrial dynamics can regulate oxidative phosphorylation is still unknown. The purpose of this proposal is to uncover the basic molecular mechanism of mitochondrial metabolism and how this is regulated by mitochondrial dynamics. We have recently uncovered that the mitochondrial-shaping GTPase protein OPA1 can dictate the bioenergetic status of cells and mitochondrial respiratory capacity by promoting assembly of the electron transport chain (ETC) complexes (C1-C1V) into respiratory super complexes. Manipulation of OPA1, which regulates mitochondrial dynamics, can promote supercomplex assembly to enhance the efficiency of OXPHOS and reduce the generation of damaging ROS. This data provides the first evidence that mitochondrial shaping proteins play a direct role in regulating mitochondrial OXPHOS. In order to identify potential mechanisms by which OPA1 can regulate supercomplex assembly we have performed a proteomic screen using a SILACbased quantitative mass spectrometry (MS) technique. This has uncovered several candidate proteins, including the ETC Complex I assembly factor Cox7RP, that may mediate the molecular changes that OPA1 imposes on metabolism. Cox7RP promotes ETC supercomplex assembly and regulates energy metabolism, and our preliminary data shows that levels Cox7RP respond to changes in expression of mitochondrial OPA1. Therefore, we hypothesis that mitochondrial morphology can regulate OXPHOS through the interaction of the mitochondrial shaping protein OPA1 with Cox7RP. Thus the functional interaction between Cox7RP and the mitochondrial shaping protein OPA1 will be studied to understand the link between mitochondrial morphology and cellular bioenergetic states.

线粒体被经典地称为细胞能量生产者。这些动态细胞器可以通过线粒体融合蛋白MFN和OPA 1以及裂变蛋白DRP 1改变其裂变和融合活性来改变其结构。线粒体具有响应生理需求而不断修改其结构的能力，并且最近的发现表明线粒体结构和功能之间存在直接联系。例如，我们已经证明，在某些条件下，线粒体结构的变化可以改变能量代谢，以促进有效的ATP产生，同时减少活性氧（ROS）。在分子水平上，线粒体的效率通过增强电子传递链（ETC）复合物（称为呼吸超复合物）的相互组装来改变。然而，线粒体动力学变化如何调节氧化磷酸化的分子机制仍然未知。该提案的目的是揭示线粒体代谢的基本分子机制以及线粒体动力学如何调节线粒体代谢。我们最近发现，血管成形GT3蛋白OPA 1可以通过促进电子传递链（ETC）复合物（C1-C1 V）组装成呼吸超复合物来决定细胞的生物能量状态和线粒体呼吸能力。操纵OPA 1，调节线粒体动力学，可以促进超复合物组装，以提高OXPHOS的效率，减少破坏性ROS的产生。该数据提供了线粒体成形蛋白在调节线粒体OXPHOS中发挥直接作用的第一个证据。为了确定OPA 1可以调节超复合物组装的潜在机制，我们使用基于SILAC的定量质谱（MS）技术进行了蛋白质组学筛选。这已经发现了几种候选蛋白，包括ETC复合物I组装因子Cox 7 RP，其可能介导OPA 1对代谢施加的分子变化。Cox 7 RP促进ETC超复合物的组装并调节能量代谢，我们的初步数据显示Cox 7 RP水平响应于线粒体OPA 1表达的变化。因此，我们假设线粒体形态可以通过线粒体成形蛋白OPA 1与Cox 7 RP的相互作用来调节OXPHOS。因此，将研究Cox 7 RP和线粒体成形蛋白OPA 1之间的功能相互作用，以了解线粒体形态和细胞生物能量状态之间的联系。